The proposed research is aimed at developing radiopharmaceuticals that readily enter the brain and selectively localize in the white matter via direct binding to myelin membranes. Abnormality and changes associated with myelin membranes in the central nervous system play a key role in the pathogenesis of multiple sclerosis and other related neurodegenerative disorders. Thus, direct assessment of myelin content in vivo has been an important goal in protection and repair of axonal damage. However, the lack of molecular probes has limited the progress of myelin imaging and hindered efficacy evaluation of novel myelin repair therapies currently under development. To meet this need, we plan to develop myelin-imaging agents uniquely suited for use in clinical imaging modalities such as positron emission tomography (PET). We hypothesize that small-molecule PET probes can be developed, which will freely enter the brain, directly and selectively bind to myelin membranes. To test this hypothesis, we have identified some lead compounds with promising binding properties for in vivo studies, which allows us to address the following specific aims: 1) Rationally design and synthesize a selected series of myelin-imaging agents and quantitatively evaluate their binding properties in vitro for structure-activity relationship studies;2) Radiolabel selected agents with positron-emitting 11C or 18F and assess the in vivo binding properties in animal models of demyelination to determine the rates of brain entry, clearance, and specific retention in the brain;3) Evaluate the pharmacokinetic profiles and metabolism of selected myelin-imaging agents through PET studies in non-human primates for potential application in human subjects. It is anticipated that completion of the project will lead to the development of imaging markers that are suitable for application in human subjects. PUBLIC HEALTH RELEVANCE: This research project has following important impacts on public health: 1) facilitation of efficacy evaluation of therapies currently under development that are aimed at prevention of axonal damage and myelin repair;2) direct correlation of myelin changes with clinical outcomes;3) aid in early and accurate diagnosis and subtyping of MS and related diseases.